The present invention relates to a method and apparatus for producing a pharmaceutical granulation product which is typically compressed into tablets or filled into hard gelatin capsules. More particularly, it pertains to a single-pass automated system and an apparatus for continuous production of a pharmaceutical granulation which incorporates wet granulation, drying, and milling.
Granulation is a critical unit operation in the manufacture of solid oral dosage forms. Even with constant improvements in tableting equipment for automating production and increasing product output, powder granulations must still possess specific physical properties to ensure smooth operations in downstream processing. Thus, consistent product quality is often the most important motivation that guides advances in granulation techniques. Other significant goals are maintaining regulatory compliance, reducing cycle times, increasing process efficiency, and achieving production cost savings.
Advancements in wet granulation technology include high shear mixer granulators, single pot processing with a high shear mixer granulator and microwave drying, and a high shear granulator integrated with a fluid bed dryer, such as a semi-continuous multi cell apparatus. While these techniques provide some advantages over previously used granulation methods, there are specific shortcomings with each technique and, most importantly, none provide a true continuous granulation process starting with individual ingredients or a powder blend.
For example, in a single pot microwave based granulator using a high shear mixer, blending and agglomeration are accomplished by an impeller; while a chopper imparts high mechanical agitation to the blend of ingredients. Even though this granulator allows short processing time and the option of drying within the same equipment, the granulator is not efficient in granulating cohesive materials; it produces non-uniform shaped and sized granules; it degrades fragile granules; it allows uncontrolled granule growth; and it produces granules with low porosity.
In addition, Glatt GmbH (of Binzen Germany) has disclosed the use of a semi-continuous system (the xe2x80x9cGlatt Multicell GMCxe2x80x9d) in which small batches of raw materials are conveyed in successive batches into a high shear, mixer-granulator which mixes and granulates the materials. The wet granulation is sequentially vacuum conveyed through a series of three fluid bed dryers for drying. Each unit operation occurs sequentially as the mini-batch moves through the system.
For drying ingredients during the manufacture of pharmaceutical products, conduction and convection have been the two most prevalent heating methods used. For drying pharmaceutical solids, use of convection is preferred to use of conduction because conductive heat transfer requires temperatures that would potentially result in product degradation. Nevertheless, in convective drying, either a high volume of air flow or long residence times are required to achieve the required reduction in moisture levels. In some instances, vacuum conditions are used to further enhance the removal of the evaporated moisture. The high volume of air flow or long residence times from convective drying can degrade or otherwise damage a pharmaceutical product produced therefrom. To a lesser degree, microwave energy has also been used, but only in batch mode. At present, no conventional drying systems provide a true single pass drying process with a first in-first out principle.
Therefore, there exists a need for a granulation process, a drying process, and a single pass, fully automated, continuous system which enables production of pharmaceutical granulation with consistent physical properties.
The present invention provides a single pass continuous, automated process for producing a granulation product, which can be further processed to make a solid oral dosage form, such as a tablet or capsule.
In one embodiment, the present invention comprises a twin screw wet granulator-chopper (TSWGC), to which active ingredient(s) and solid and liquid additives are fed, which mixes, granulates, and wet mills those components to form a granulation product.
In another embodiment, the present invention comprises a drying apparatus which dries granulation using dielectric energy, such as radio frequency energy, low frequency (conventional) microwave energy, or high frequency (millimeter wave) microwave energy, in a continuous, single pass mode, optionally incorporating a product isolation tunnel.
In a further embodiment, the present invention comprises integrated, automated process control of the components of the system such that key process parameters and product properties are monitored along the length of the system; for example, the moisture content of the granulation and the uniformity of the distribution of active ingredient(s) are monitored on-line, and feedback is provided to the individual components which adjusts conditions to achieve optimal parametric release of the product.
It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.